Recent studies have demonstrated widespread apoptotic neurodegeneration induced in the developing rodent brain by transient exposure to various agents that suppress neuronal activity, including NMDA glutamate antagonists, GABAA agonists, ethanol, and sodium channel blockers. The potential neurotoxic effects of MgSO4 have important public health implications due to its frequent use in obstetrics for preterm labor and pre-eclampsia/eclampsia resulting in fetal exposure during the synaptogenic period. Although Mg++ has been used in obstetrics for over 60 years, there is a lack of studies addressing the effects of increased Mg++ on the fetal brain. Mg++ has inhibitory properties at numerous cellular membrane receptors and ion channels, and can enhance surface charge screening effects. I have developed preliminary in vivo evidence that exposure to Mg++ can trigger apoptotic neurodegeneration in the developing rodent brain. In order to expand upon these in vivo findings, I have performed experiments exposing cultured hippocampal neurons to Mg++ and found similar neurodegenerative effects. I hypothesize that because of its intrinsic neuroinhibitory properties, Mg++ at non-physiologically high concentrations can suppress neuronal activity to a degree that is sufficient to precipitate neuroapoptosis. The Aims of the proposed research are: 1) to further characterize the neurodegenerative reaction induced in the developing mouse brain by Mg++ with respect to nature, pattern, pattern, time-course and age specificity; 2) determine dose-response parameters in vitro and in vivo, including lowest effective dose, and compare this with doses to which the developing human brain is sometimes exposed; 3) investigate mechanisms(s) and protective strategies in both in vitro and in vivo models. In the course of this work I will learn various histological methods, including electron microscopy and immunohistochemistry; stereologic techniques to quantitate neuronal injury; western blotting for evaluating biochemical pathways; transgenic animals, electrophysiology, and Ca++ and Mg++ imaging to aid in mechanistic studies; and pharmacological interventions to evaluate protective strategies. In addition, I will develop an understanding of neuroanatomy, neurochemistry, toxicokinetics and toxicodynamics, and statistical methods. My preceptors, Dr. John Olney, Dr. Eugene Johnson and Dr. Steve Mennerick, will provide close guidance and supervision during the proposed research period. [unreadable] [unreadable]